European Journal of Clinical Investigation

Strategies for the use of COVID‐19 vaccines in children and young adults (in particular university students) are hotly debated and important to optimize. As of late August 2021, recommendations on the use of these vaccines in children vary across different countries. Recommendations are more uniform for vaccines in young adults, but vaccination uptake in this age group shows a large range across countries. Mandates for vaccination of university students are a particularly debated topic with many campuses endorsing mandates in the USA in contrast to European countries, at least as of August 2021. The commentary discusses the potential indirect impact of vaccination of youth on the COVID‐19 burden of disease for other age groups and societal functioning at large, estimates of direct impact on reducing fatalities and nonlethal COVID‐19‐related events in youth, estimates of potential lethal and nonlethal adverse events from vaccines and differential considerations that may exist in the USA, European countries and nonhigh‐income countries. Decision‐making for deploying COVID‐19 vaccines in young people is subject to residual uncertainty on the future course of the pandemic and potential evolution towards endemicity. Rational recommendations would also benefit from better understanding of the clinical and sociodemographic features of COVID‐19 risk in young populations and from dissecting the role of re‐infections and durability of natural vs. vaccine‐induced immunity.

Abstract. We studied the acute effects of intravenous infusions of chlorpromazine hydrochloride on bile salt synthesis, bile formation and biliary lipid secretion in the alert female Rhesus monkey prepared with a total biliary fistula and in a steady bile salt secretory state. In twelve studies (three animals), five doses of radio‐labelled chlorpromazine hydrochloride (1–10 mg = 2.8–28 μmol/kg) were infused intravenously for 1 h in random order. Cholestasis was induced within minutes in all experiments. The radiolabel appeared rapidly in bile, with similar recoveries in bile and urine and a 90% total cumulative output in 4 days. Both bile flow, bile salt and other biliary lipid outputs were inhibited in a dose related and reversible manner. The apparent bile salt independent bile flow was consistently abolished, and a prompt return to basal values occurred when biliary concentrations of the drug and metabolites fell below 1–2 mM. When chlorpromazine hydrochloride was infused at three doses (2.5, 5.0 and 10.0 mg = 7–28 μmol/kg) during constant intravenous infusion of ¹⁴C sodium taurocholate (300 μmol/h), bile flow, total bile salt output and ¹⁴C taurocholate output decreased within minutes. This was accompanied by a progressive rise in the serum ¹⁴C taurocholate concentration. After 90 min the taurocholate specific activity in bile increased significantly indicating that bile salt synthesis was inhibited. Secretion of retained bile salts and reversal of inhibition of bile salt synthesis occurred with time: the course of both events was correlated with the dose of the drug.

Thus, in monkeys, chlorpromazine hydrochloride induces reversible, dose related cholestasis involving suppression of the bile salt dependent and independent flow, inhibition of bile salt synthesis and impairment of biliary lipid secretion. We suggest that these effects are due to both bile salt‐chlorpromazine interactions and the effect of the latter on canalicular and other membranes.

There is recent evidence that upper‐gut motor abnormalities may be present in coeliac disease. However, to date, the pathophysiological mechanisms responsible for the above have not been explored. The purpose of the present study was to investigate upper‐gut motor activity in coeliac disease and explore the role played by the autonomic nervous system in motility disturbances. Thirty untreated adult coeliac patients were recruited into the study. Oesophageal manometry and cardiovascular autonomic tests were performed in all patients; oesophageal pH‐metry was carried out in 20 patients, gastrointestinal manometry in eight and scintigraphic gastric emptying in 13. Oesophageal motor abnormalities were detected in about 50% of patients, pH‐metry was abnormal in 30% of them, and up to 75% of coeliac patients displayed gastrointestinal motility alterations. Delayed gastric emptying was documented in about 50% of patients and was correlated with manometric post‐prandial hypomotility. Autonomic tests were positive in 45% of patients as a group, and reached pathological score in 19% of them. Autonomic score correlated significantly with the percentage of bi‐peaked waves and with the number of fasting intestinal clusters. This study confirms that upper‐gut motor abnormalities are frequently present in adult coeliac disease. Extrinsec autonomic neuropathy may play a role, although other pathophysiological mechanisms are likely to occur.

Despite criticism regarding its clinical relevance, the concept of the metabolic syndrome improves our understanding of both the pathophysiology of insulin resistance and its associated metabolic changes and vascular consequences. Free fatty acids (FFA) and tumour necrosis factor‐alpha (TNF‐α) play prominent roles in the development of insulin resistance by impairing the intracellular insulin signalling transduction pathway. Obesity is an independent risk factor for cardiovascular disease and strongly related to insulin resistance. In case of obesity, FFAs and TNF‐α are produced in abundance by adipocytes, whereas the production of adiponectin, an anti‐inflammatory adipokine, is reduced. This imbalanced production of pro‐ and anti‐inflammatory adipokines, as observed in adipocyte dysfunction, is thought to be the driving force behind insulin resistance. The role of several recently discovered adipokines such as resistin, visfatin and retinol‐binding protein (RBP)‐4 in the pathogenesis of insulin resistance is increasingly understood. Insulin resistance induces several metabolic changes, including hyperglycaemia, dyslipidaemia and hypertension, all leading to increased cardiovascular risk. In addition, the dysfunctional adipocyte, reflected largely by low adiponectin levels and a high TNF‐α concentration, directly influences the vascular endothelium, causing endothelial dysfunction and atherosclerosis. Adipocyte dysfunction could therefore be regarded as the common antecedent of both insulin resistance and atherosclerosis and functions as the link between obesity and cardiovascular disease. Targeting the dysfunctional adipocyte may reduce the risk for both cardiovascular disease and the development of type 2 diabetes. Although lifestyle intervention remains the cornerstone of therapy in improving insulin sensitivity and its associated metabolic changes, medical treatment might prove to be important as well.

Steroids have the ability to alter adipose tissue distribution. Controversy exists as to whether these effects of sex hormones (oestrogen, progesterone and testosterone) on human adipose tissue are indirect or direct, as only very few studies have focused on steroid receptor status in human adipose tissue. In the present study, we reinvestigated steroid receptor status in human mature adipose tissue and human preadipocytes. Oestrogen, glucocorticoid and androgen receptors were found in human mature adipocytes from both women and men. The receptors were detected by ligand binding. Furthermore, the existence of the receptors was confirmed by demonstrating that adipocytes contained mRNA encoding the receptors. cDNA was generated using reverse transcriptase (RT) followed by polymerase chain reaction (PCR) amplification using specific primers (RT–PCR) for the specific steroid receptors. Adipocytes did not contain mRNA encoding the progesterone receptor (PR), and no progesterone binding was detectable in human adipocytes. Human preadipocytes contained glucocorticoid receptor (GR) mRNA and androgen receptor (AR) mRNA, whereas we were unable to detect oestrogen receptor (ER) mRNA and progesterone mRNA in human preadipocytes. In conclusion, oestrogen glucocorticoid and androgen receptors are present in mature adipocytes from subjects of both sexes, whereas adipocytes do not contain progesterone receptors. In preadipocytes, only glucocorticoid receptors and androgen receptors are present, whereas oestrogen receptors and progesterone receptors are not present.

Little is known about the onset and degree of biochemical and functional alterations in calcium metabolism during microgravity.

To evaluate the effect of microgravity on intestinal calcium absorption and calcium‐regulating hormones under metabolic ward conditions.

Fractional calcium absorption (Fc₂₄₀ in percentage of dose administered) was determined pre‐flight, in‐flight and post‐flight, by use of a stable strontium test in one cosmonaut who spent 20 days in space. Moreover, a sequence of blood samples was collected for the determination of serum parathyroid hormone (PTH), 25‐hydroxyvitamin D, calcitriol and serum C‐telopeptide (CTx, biomarker of bone resorption) levels. During all periods of data collection, calcium intake was held constant at a minimum level of 1·000 mg day⁻¹ and a daily supplement of 16·6 µg vitamin D₂ was given. Personal ultraviolet (UV) light exposure was measured during the whole mission using a biologically weighting UV dosimeter.

Fc₂₄₀ was markedly reduced on flight day 19 (4·4%) as compared to pre‐flight and post‐flight data (13·4% and 17·2%, respectively). Serum calcitriol levels fell from 40·6 pg mL⁻¹ (mean pre‐flight level) to 1·3 pg mL⁻¹ on flight day 18 and returned into the normal range after recovery. Serum CTx increased during the flight, while serum PTH and 25‐hydroxyvitamin D levels did not change significantly.

Intestinal calcium absorption can be diminished after only three weeks of microgravity. Changes are associated with a severe suppression of circulating calcitriol levels, but are independent of exogenous vitamin D supply and serum PTH levels.

Making sense of rapidly evolving evidence on genetic associations is crucial to making genuine advances in human genomics and the eventual integration of this information in the practice of medicine and public health. Assessment of the strengths and weaknesses of this evidence, and hence the ability to synthesize it, has been limited by inadequate reporting of results. The STrengthening the REporting of Genetic Association studies (STREGA) initiative builds on the STrengthening the Reporting of OBservational Studies in Epidemiology (STROBE) Statement and provides additions to 12 of the 22 items on the STROBE checklist. The additions concern population stratification, genotyping errors, modelling haplotype variation, Hardy–Weinberg equilibrium, replication, selection of participants, rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods, relatedness, reporting of descriptive and outcome data and the volume of data issues that are important to consider in genetic association studies. The STREGA recommendations do not prescribe or dictate how a genetic association study should be designed, but seek to enhance the transparency of its reporting, regardless of choices made during design, conduct or analysis.